The main indications for the prescription of non-steroidal anti-inflammatory drugs (hereinafter NSAIDs) are inflammatory processes of different nature and localization, pain and fever. NSAIDs are one of the most widely used groups of drugs. For example, NSAIDs are prescribed to about 20% of inpatients with various diseases of internal organs [Guidelines for Pre-clinical Drug Research. Part one/edited by A. N. Mironov.—M.: Grif and K Publ., 2012. p. 944].
The main element of the mechanism of action of NSAIDs is the suppression of the synthesis of inflammatory mediators—prostaglandins. During the process of alteration (the first stage of inflammation) the cell membrane releases phospholipids which under the action of the enzyme of phospholipase A2 are metabolized to arachidonic acid. Arachidonic acid, in turn, is metabolized in two ways: cyclooxygenase (COX) and lipoxygenase (LOX). NSAIDs inhibit only COX, so they block the development of only the second stage of inflammation [Guidelines for Pre-clinical Drug Research. Part one/edited by A. N. Mironov. —M.: Grif and K Publ., 2012. p. 944].
There are 2 COX isoenzymes: COX-1 (constitutional, normally existing) controls the production of prostanoids that regulate physiological functions of the stomach, vessels and kidneys; COX-2 (induced) is involved in the synthesis of prostaglandins in inflammation. COX-2 is normally absent and is formed under the influence of tissue factors that induce an inflammatory response (cytokines, etc.). It is believed that the anti-inflammatory effect of NSAIDs is due to the inhibition of COX-2, and the side effects are due to the inhibition of COX-1 [Guidelines for Pre-clinical Drug Research. Part one/edited by A. N. Mironov. —M.: Grif and K Publ., 2012. p. 944].
The most known NSAIDs are ketoprofen (3-benzoyl-alpha-methylbenzene acetic acid), ibuprofen ((RS)-2-(4-isobutylphenyl) propionic acid), diclofenac (2-[(2,6-dichlorophenyl) amino] benzene acetic acid), indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetic acid) and naproxen ((S)-6-methoxy-α-methyl-2-naphthalenacetic acid). Currently naproxen occupies one of the leading positions in the group of NSAIDs, because it has a longer effect than other NSAIDs and is well tolerated [Mashkovsky M. D. Lekarstvennye sredstva. [Medicinal Drugs.] 16th ed., revised and modified—M.: Novaya Volna [New Wave] Publ., 2012. p. 1216].
The disadvantage of known to date NSAIDs, namely non-selective cyclooxygenase inhibitors, is their pronounced gastric toxicity [Handa, O. The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium/O. Handa, Y. Naito, A. Fukui, T. Omatsu, T. Yoshikawa//J. Clin. Biochem. Nutr.—2014.—V. 54, N. 1.—P. 2-6.]. Selective inhibitors of COX-2 are less gastrotoxic, but their negative effects on the cardiovascular system are known [Singh, B. K. Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity/B. K. Singh, S. E. Hague, K. K. Pillai//Expert. Opin. Drug Metab. Toxicol.—2014.—V. 10, N. 2.—P. 143-156.]. Thus, on the date of submission of the application materials, the problem of reducing the side effects of both types of NSAIDs—selective and non-selective cyclooxygenase inhibitors—remains unresolved.
Thus, the development of safe and effective NSAIDs is one of the most important tasks of pharmacotherapy and health care in general.
In the applicant view, based on the analysis of the level of technology, the most promising direction of development of anti-inflammatory drugs is search for non-selective NSAIDs. At the same time, as noted above, developers face the task of reducing side effects, the main of which is gastric toxicity.
Protection of carboxyl group of non-selective COX inhibitors is one of the main ways to reduce toxicity of this group of NSAIDs. Ester protection is the most frequently used for this purpose [Liu, W. Synthesis and biological evaluation of curcumin derivatives containing NSAIDs for their anti-inflammatory activity [Text]/W. Liu, Y. Li, Y. Yue, et al.//Bioorg. Med. Chem. Lett.—2015.—V. 25, N. 15.—P. 3044-3051.]. NSAIDs esters are typical promedications, which in the gastrointestinal tract (hereinafter referred to as the GIT) undergo enzymatic hydrolysis with gradual release of NSAIDs, providing a prolonged effect of the drug. In addition, promedications based on esters better penetrate cytoplasmic membranes of cells, thus having less irritating effect on the mucous membrane of the GIT. Ascorbic acid esters with NSAIDs are known to be derivatives of arilacetic or arylpropionic acids, such as ibuprofen, ketoprofen, naproxen and their salts [EP 2431361, published on 21 Mar. 2012]. For the treatment of arthritis, pain and inflammatory processes was proposed 2-methansulfonatethyl ester of naproxen together with H2 receptors antagonist [WO 200810106441, published 21 Aug. 2008]. This modification of NSAIDs leads to a decrease in gastric toxicity, but at the same time significantly reduces the therapeutic effect. For this reason, these compounds have not been included in clinical practice.
The closest combination of coinciding features and achieved technical result to the claimed invention is the technical solution described in the invention in the patent RU 2513089 “Non-steroidal anti-inflammatory drugs based on pyridoxine derivatives”, the essence of which are pyridoxine derivatives of the general formula (I)
where:when R2+R3=—C(CH3)2— or —CH (CH3)—;
when R1=H; R3=H;
having anti-inflammatory activity.
The prototype version containing three fragments of naproxen is an effective anti-inflammatory compound. In particular, it has a pronounced anti-inflammatory effect on the model of subacute (formalin) edema in vivo.
However, on the model of acute (carrageenin) edema in vivo this prototype was not effective enough. It is important to note that the prototype does not have at the same time a set of properties of the claimed invention, namely high anti-inflammatory (on the model of acute (carrageenin) edema in vivo), analgesic and antipyretic activity combined with low toxicity, including gastric toxicity. For this reason, the applicant does not consider this prototype as a comparison drug, instead of it a modern non-steroidal anti-inflammatory drug naproxen and its analogues are used for this purpose (table 3).
The claimed composition of the claimed invention differs from that described in the prototype by the presence of an additional fragment of naproxen, which, in the applicant's experimentally grounded view, causes the appearance of pharmacologically significant positive effects. Thus, the combination in the claimed molecule of covalent ester bonds split under physiological conditions and non-covalent ionic bond linking fragments of naproxen and pyridoxine, leads to the emergence of synergistic effects that are not obvious to a specialist. These effects are expressed in increased anti-inflammatory, analgesic and antipyretic activity, as well as in significantly reduced gastric toxicity and acute toxicity. In particular, the claimed compound of formula I against the background of reduced gastric toxicity and acute toxicity ensures a rapid onset of a pronounced anti-inflammatory effect on the model of both acute and subacute edema in vivo, whereby the applicant can resolve the seemingly insurmountable problem typical of both the prototype and many other NSAIDs including naproxen (the latter is also the prototype of the claimed invention).